The present invention generally relates to the aging or damage of hair, nails, tissues, organs and cells and, more particularly, to the rejuvenation of hair, nails, tissues, cells, and organs by improving the deformability and diffusion coefficient of hair, nails, tissues, cells, and organs in humans and animals (including companion animals and live stock).
Various changes in the biomechanical and other functional properties of hair may occur with aging and diseases. Undesirable changes may include deterioration in manageability, including decreased stability and brittle hair. Typically, these detrimental changes may be due to: (a) physically or chemically damaged hair; (b) physiologically aged hair; and/or (c) diseased hair (e.g. hair of diabetics). Hair may be physically damaged from the normal grooming process of shampooing, combing, drying (e.g. hot air blow drying), and/or brushing. In addition to this physical damage of hair, hair may also be damaged by chemical action such as by exposure to sunlight and contact with water containing chemically reactive agents such as oxidizers (e.g bleaching and/or dyeing of hair). Also, the repeated use of permanent waving compositions on the hair fibers may cause damage to the hair especially if not used according to directions. Bleached hair is often characterized as being dry, brittle, and overly coarse. Finally, with the aging process, hair may become dry, brittle and overly coarse.
For nails, deterioration in the biomechanical and other functional properties may also result in undesirable nail problems. Conventionally, the term xe2x80x9cnailxe2x80x9d has meant the horny cutaneous plate on the dorsal surface of the distal end of a finger or toe, or the corresponding appendages in animals. Specifically, in humans, the hardness and strength of the nails is particularly important not only for the beauty of their appearance, but for the well-being of the individual. Embrittlement of the nails is normally associated with aging. However, various activities also expose nails to a number of materials which may adversely affect the nail""s biomechanical and other functional properties. For example, occupational exposure to extensive or constant wetting of the hands with soaps, detergents, solvents, chemical hair waving and coloring lotions, and insults from deliberate cosmetic applications, such as manicuring, or any like products can lead to drying, brittleness, cracking, laminating, splitting, ridging and similar damage. Additionally, certain diseases may also lead to nail embrittlement or associated disfigurement owing to weakening of nail hardness and strength. Moreover, the appearance of fingernails and toenails of humans are frequently enhanced with decorative nail-care cosmetics, such as nail polishes, nail polish removers, nail polish bases, alkaline cuticle removers and the like. Overuse of these products can alter the nail, causing it to weaken, soften, split and break.
With respect to tissues, cells and organs, transplantation of these materials has become a routine means of treating certain diseases and other conditions. Transplantation requires a ready source of organs, such as kidney, pancreas, liver, heart, etc., from living persons or cadavers. Conventionally, most vital organs, cells and tissues, which are used for transplantation, are obtained from heart beating cadavers and preserved for variable periods of time prior to their transplantation. However, preservation methods merely attempt to maintain the present condition of the organ, cell or tissue. For this reason, the majority of organs, cells and tissues that are used for transplantation presently come from younger individuals who typically have tissues, cells and organs that have not been detrimentally affected by age or disease.
In contrast, because of the aging process or disease, older individuals have a deterioration in the biomechanical (e.g. deformability) and other functional properties of their cells, tissues and organs. For this reason, decreased deformability is associated with impaired tissue or organ functionality in itself, as optimal biomechanical function is demonstrated at deformability levels measured in young individuals and diminishes with progressively decreasing levels of deformability. Thus, at the present time, older individuals typically can not be candidates for organ, tissue or cell donation because preservation solutions merely attempt to preserve the present condition of the organ, cell or tissue.
Conventionally, two typical methods of preserving organs, cells and tissues for transplantation are continuous pulsatile perfusion and simple hypothermic storage in a preservation solution. In pulsatile perfusion, the organ is subjected to pulsatile flow of a perfusate under hypothermic conditions such that the organ membranes receive sufficient oxygenation. Typically, the perfusate contains albumin and lipids. With simple hypothermic storage, organs are removed from a cadaver donor and rapidly cooled. Rapid cooling is achieved by external cooling and by perfusion with a preservation solution to lower the internal temperature of the organ. The organ is then stored immersed in the preservation solution at temperatures of about 0xc2x0-4xc2x0 C. Two conventional glucose preservation flush solutions are the Collins (G. M. Collins, The Lancet, 1969, 1219-1222) and the Euro-Collins (J. P. Squifflet et al, Transplant. Proc., 1981, 13:693-696) solutions. These solutions resemble intracellular fluid and contain glucose as an osmotic agent. Despite their widespread use, the Collins and Euro-Collins preservation solutions do not typically provide adequate preservation for storage times greater than about 48 hours. For example, kidneys stored in Collins solution for 24 hours may exhibit considerable damage to the nephrons. This damage included degradation of cells lining the proximal tubules, extensive swelling and rupturing of cells lining the ascending distal tubules, degeneration of glomerular epithelial and endothelial cells and accumulation of flocculent cytoplasmic debris in the capsular spaces of Bowman. (P. M. Andrews et al, Lab. Invest., 1982, 46:100-120). In addition to glucose flush solutions, high osmolality preservation solutions have been prepared using raffinose and lactobionate as in the UW preservation solution (R. J. Ploeg et al, Transplant. Proc., 1988, 20 (suppl 1) 1:935-938), mannitol in the Sacks solution (S. A. Sacks, The Lancet, 1973, 1:1024-1028), sucrose in the phosphate buffered sucrose (PBS) preservation solution (F. T. Lam et al, Transplantation, 1989, 47:767-771) and the histidine buffered HTK solution of Bretschneider (N. M. Kallerhoff et al, Transplantation, 1985, 39:485-489). Other examples are solutions that contain synthetic hydroxyethyl starch (HES) as an osmotic colloid.
In accordance with the present invention, a novel method and composition are disclosed for the xe2x80x9crejuvenationxe2x80x9d of hair, nails, tissues, cells and organs by ex-vivo treatment. In particular, the composition comprises compounds for the ex-vivo treatment of hair, nails, tissues, cells and organs to improve the biomechanical and other functional properties of hair, nails, tissues, cells and organs. More particularly, for hair and nails, the composition and method of the present invention comprises compounds for rejuvenating: (a) damaged hair or nails; (b) physiologically aged hair or nails; and/or (c) diseased hair or nails (e.g. diabetes). For tissues, cells and organs, the composition and method of the present invention comprises compounds for rejuvenating tissues, cells and organs by improving the deformability and/or diffusion coefficient of tissues, cells and organs from a state of decreased deformability and impaired diffusional characteristics, as typically observed in cells, tissues or organs of older individuals, to a state of increased deformability and improved diffusional characteristics, as commonly seen in cells, tissues and organs of healthy and young individuals (i.e 20 years old).
Decreased deformability is associated with impaired tissue or organ functionality in itself, as optimal biomechanical function is demonstrated at deformability levels measured in young individuals and diminishes progressively with age. It is believed that the aging process, in addition to modifying the deformability, also induces additional specific impairments in the functionality of cells, tissues and/or organs that are not directly related to deformability. It is further believed that this impairment in functionality is related to an altered diffusion coefficient of molecules across intracellular and extracellular spaces. The altered ability of molecules to traverse intra- and extracellular spaces may affect signaling functions of hormones and cytokines, transportation of oxygen and nutrients from the vascular space to the cell, and cellular metabolism.
Commonly used methods to determine deformability include ultrasonographic techniques and the measurement of volume-pressure and stress-strain relationships. Commonly used methods to measure the diffusion coefficient of molecules across intracellular and extracellular spaces include the determination of the reaction time of biomolecular feed-back mechanisms based on the diffusion of molecules across a cellular, tissue and/or organ space to reach a target response element and the direct measurement of the diffusion rate of certain molecules across biological spaces. Examples of methods to determine the biomolecular feed-back mechanisms include, but are not limited to, the following: (a) hypothalamic-pituitary axis: growth hormone, ACTH, TSH, or prolactin; (b) pituitary-adrenal axis: cortisol; (c) pituitary-thyroid axis: thyroxin; and (d) pituitary-gonadal axis: sex hormones, LH, and FSH. Examples of methods to determine the diffusion rate of certain molecules across biological spaces include, but are not limited to, the following: arterio-alveolar oxygen and carbon dioxide gradients; insulin resistance; and arterio-venous oxygen gradient (e.g., heart, muscle).
In particular, the compositions comprise compounds for the ex-vivo treatment of hair, nails, organs, cells and tissues to rejuvenate them by changing deformability and increase the tissue diffusion coefficient. This treatment is accomplished by bathing or perfusing the biological material outside of the body. The compounds are members of the class of compounds known as thiazoliums.
In one embodiment, the compositions comprise thiazolium compounds having the following structural formula (I): 
wherein R1 and R2 are independently selected from the group consisting of hydrogen, hydroxy(lower alkyl), lower acyloxy(lower alkyl), lower alkyl, lower alkenyl, or R1 and R2 together with their ring carbons may be an aromatic fused, ring, optionally substituted by one or more amino, halo or alkylenedioxy groups;
Z is hydrogen or an amino group;
Y is amino, a group of the formula xe2x80x94CH2C(xe2x95x90O)xe2x80x94R wherein R is a lower alkyl, alkoxy, hydroxy, amino or aryl group; said aryl group optionally substituted by one or more lower alkyl, lower alkoxy, halo, dialkylamino, hydroxy, nitro or alkylenedioxy groups;
or a group of the formula xe2x80x94CH2Rxe2x80x2 wherein Rxe2x80x2 is hydrogen, or a lower alkyl, lower alkynyl, or aryl group;
or a group of the formula xe2x80x94CH2C(xe2x95x90O)xe2x80x94N(Rxe2x80x3)Rxe2x80x2xe2x80x3 wherein (a) Rxe2x80x3 is hydrogen and Rxe2x80x2xe2x80x3 is a lower alkyl group, optionally substituted by a C6-C10 aryl group, or a C6-C10 aryl group, said aryl groups optionally substituted by one or more lower alkyl, halo, or (lower alkoxyl)carbonyl groups; or (b) Rxe2x80x3 and Rxe2x80x2xe2x80x3 are both lower alkyl groups;
X is a halide, tosylate, methanesulfonate, mesitylenesulfonate ion, or other pharmaceutically acceptable anion and mixtures thereof, and a carrier therefor.
In another embodiment, the composition comprises compounds having the following structural formula (II): 
wherein R1 and R2 are independently selected from the group consisting of hydrogen and an alkyl group optionally substituted by a hydroxy group;
Y is a group of the formula xe2x80x94CH2C(xe2x95x90)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups;
or a group of the formula xe2x80x94CH2C(xe2x95x90O)xe2x80x94NHRxe2x80x2 wherein Rxe2x80x2 is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups;
and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion, or other pharmaceutically acceptable anion.
The present invention also relates to a method for treating hair and nails and for the ex-vivo rejuvenation of organs, cells and tissues by contacting the hair and/or nails or ex-vivo organs, cells or tissues with a sufficient amount of one or more of the compounds of the present invention, or a composition containing a sufficient amount to achieve the desired result.